The naturally occurring compounds of formula I and their semi-synthetic analogs are very active antihypercholesterolemic agents that function by limiting the cholesterol biosynthesis by inhibiting the HMG-CoA reductase enzyme.
Compounds of formula Ia, shown in page 9, include the natural fermentation products like mevinolin (disclosed in U.S. Pat No. 4,231,938 and also known as lovastatin), compactin (disclosed in U.S. Pat No. 3,983,240) and a variety of semi-synthetic and totally synthetic analogs thereof, all having the natural 2-methylbutyrate side chain.
Compounds of formula IIa, shown in page 9, having a 2,2-dimethylbutyrate side chain (e.g., simvastatin) are known to be more active inhibitors of HMG-CoA reductase than their 2-methylbutyate analogs and thus of greater utility in the treatment of artherosclerosis, hyperlipemia, familial hypercholesterolemia and similar disorders.
It has been proved that products having a 2,2-dimethylbutryate side chain are more active inhibitors than their analogs. The introduction of simvastatin (IIa) into the market as a more potent HMG-CoA reductase inhibitor than lovastatin (Ia) has provided a need for a high yielding process which is more economically efficient and environmentally sound than those disclosed in the prior art.
Compounds of formula Ia (e.g. simvastatin) with the 2,2-dimethylbutyrate side chain and processes for their preparation are disclosed in U.S. Pat No. 4,444,784 and EPO patent specification No. 33538. The route described are both tedious and cumbersome and gives very poor over all yields.
Simvastatin has also been prepared by the xcex1-alkylation of the ester moiety as described in U.S. Pat. Nos. 4,582,915 and 4,820,850.
U.S. Pat. No. 4,582,915 discloses the direct methylation in a single step using a metal alkyl and a methyl halide. The process suffers from poor conversion coupled with many side reactions which complicate both isolation and purification of the final product, simvastatin.
The U.S. Pat. No. 4,820,850 describes a good conversion to simvastatin using a single charge of the amide base and alkyl halide. However, the process suffers from a large number of steps and hence affecting the over all yield. Further, the process utilizes a highly expensive silylating agent to protect the hydroxyl groups thus rendering the route cost ineffective.
Recent patents like U.S. Pat. Nos. 5,763,653 and 5,763,646 describes the synthesis of the simvastatin from mevinolinic acid or the salt of mevinolinic acid as the starting material. U.S. Pat. No. 5,763,653 which describes the synthesis of simvastatin from the lovastatin amide prepared by treating lovastatin or the salt of mevinolinic acid with primary amine like propyl amine. The resulting lova amide has a hydrogen in the amide nitrogen which reacts with Lithium amide base thereby necessitating the need for larger equivalent of the amide base. Furthermore, the hydrogen in the amide nitrogen can react with the methyl iodide and lithium amide base and thus lead to side reactions and thereby lowering the overall yield.
These processes suffers from the fact that a primary amine is used for the ring opening and hence requires additional equivalent of the amide base reagent and suffers from other side reactions.
Accordingly the objects of the present invention is to overcome the aforesaid drawbacks by increasing the overall yield and the purity of the product and also to avoid the protection-deprotection of the hydroxy groups obtained from the lactone ring opening using highly expensive silyl or other protecting agents.
Another object of the invention is to minimize the cost of production of simvastatin by utilizing cheap raw materials and cost effective route for synthesis.
To achieve the said objective, the present invention relates to a process of manufacturing Simvastatin of formula IIa from Lovastatin characterized by the following steps:
step 1xe2x80x94converting Lovastatin to Lovastatin amide by treating Lovastatin with a secondary amine in an organic solvent,
step 2xe2x80x94reacting the said lovastatin amide with metal amide base in tetrahydrofuran (THF) followed by treatment with alkyl halide and cooling the said mixture at a temperature ranging between xe2x88x9245xc2x0 C. to xe2x88x9220xc2x0 C. till C-methylated intermediate compound is formed,
step 3xe2x80x94subjecting the said intermediate compound to hydrolysis to obtain its free acid,
step 4xe2x80x94converting the said free acid to its ammonium salt and cyclizing the said ammonium salt to obtain simvastatin.
The organic solvent used is a polar or non-polar solvent and the alkyl halide is methyl iodide.
The mixture of lovastatin amide and metal amide base is cooled at xe2x88x9230xc2x0 C.
The secondary amine is di-ethyl amine and the Lovastatin amide produced in step I is Lova-di-ethyl amide of formula IIIa wherein R1 and R2 are C2H5.
The secondary amine is pyrrolidine and the Lovastatin amide produced in step 1 is lova-pyrrolidine amide of formula Vb, wherein n=1.
The secondary amine is piperidine and the Lovastatin amide produced in step 1 is lova-piperidine amide of formula Vc, wherein n=2.
The metal amide base in THF used is prepared by adding n-butyl-lithium to pyrrolidine and cooling at a temperature ranging between xe2x88x9245xc2x0 C. to xe2x88x9220xc2x0 C. 
The C-methylated intermediate compound formed in step 2 are of formulae IVa wherein R1 =R2=C2H5; VIb wherein n=1 and VIc wherein n=2.
The novel intermediate compound of formula IIIa wherein R1 and R2=C2H5 is N,N-Diethyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S), 6(R)-dimethyl-8(S)-[{2(S)-methylbutanoyl}oxy]-1(S)-napthyl]-3(R),5(R)-hydroxyheptanoic acid amide.
The novel intermediate compound of formula Vb wherein n=1 is N-Pyrrolidinyl7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8-[{2(S)-methylbutanoyl}oxy]-1(S)-napthyl]-3(R),5(R)-dihydroxyheptanoic acid amide.
The novel intermediate compound of structural formula IVa wherein R1=R2=C2H5 is N N,N-Diethyl7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[2,2-dimethylbutanoyl}oxy]-1(S)-napthyl]-3(R),5(R)-dihydroxyheptanoic acid amide.
The novel intermediate compound of structural formula VIb wherein n=1 is N-Pyrollidinyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[2,2-dimethylbutanoyl}oxy]-1(S)-napthyl]-3(R),5(R)-dihydroxyheptanoic acid amide.
The novel intermediate compound of structural formula VIc wherein n=2 is N-Piperidinyl-7-[1,26,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[2,2-dimethylbutanoyl}oxy]-1(S)-napthyl]-3(R),5(R)-dihydroxyheptanoic acid amide.
The instant process involves only 4 steps to synthesis simvastatin (IIa).
The intermediates (III and V) avoid the formation of other side reactions with the amide base and methyl halide.
Furthermore as the present invention utilizes a secondary amine, it results in a Lovastatin amide which does not contain any hydrogen in the amine nitrogen (III and V). Thus the Lovastatin amide (III and V) requires lesser equivalents of lithium amide base and thus increases the cost effectiveness of the route.
Also, the absence of the hydrogen in the amide nitrogen prevents side reactions and thereby resulting in purer products.
Additionally, because of the higher purity of the intermediate products, the downstream processing requires fewer purification steps, thus increasing the overall yield.
According to this invention lovastation (Ia) is reacted with a diamine (secondary amine). The amine of choice is diethylamine and the intermediate obtained is the lova diethyl amide (III), wherein R1 and R2 is C2H5. Alternatively piperdine gives the lova piperdine amide (Vc) wherein n=2 and pyrrolidine gives lova pyrrolidine amide (Vb), wherein n=1.
The amide thus prepared is dissolved in dry tetrahydrofuran and cooled to xe2x88x9245xc2x0 C. to xe2x88x9220xc2x0 C. The metal amide base is prepared by adding n-BuLi to pyrrolidine and is cooled to xe2x88x9245xc2x0 C. to xe2x88x9220xc2x0 C. After about 1 hour, the alkyl halide, methyl iodide, is added and the contents are stirred for 30 min. Water is added to the reaction mixture and the layers obtained are separated. The organic layer is washed with brine solution and concentrated under reduced pressure to give an oily residue, which contains the intermediate (IVa or VIa). The crude intermediate is then hydrolyzed to give the free acid which is converted to the ammonium salt and is cyclized to give the final product, simvastatin.
The present invention is explained with the help of schemes I and II and examples.